EP0973501B1 - Aqueous suspension for nasal administration of loteprednol - Google Patents
Aqueous suspension for nasal administration of loteprednol Download PDFInfo
- Publication number
- EP0973501B1 EP0973501B1 EP98900360A EP98900360A EP0973501B1 EP 0973501 B1 EP0973501 B1 EP 0973501B1 EP 98900360 A EP98900360 A EP 98900360A EP 98900360 A EP98900360 A EP 98900360A EP 0973501 B1 EP0973501 B1 EP 0973501B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aqueous suspension
- nasal administration
- loteprednol etabonate
- suspension
- nasal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the isotonizing agent includes but is not limited to glycerin, propylene glycol, sorbitol, and mannitol.
- the buffer that can be used includes boric acid, phosphoric acid, acetic acid, and amino acids, among others.
- the stabilizer includes antioxidants (e.g.
- the aqueous suspension for nasal administration according to the present invention is preferably provided in the pH range generally used for nasal drops, i.e. pH 5-7.
- aqueous suspensions (a) through (d) prepared in Examples 1 through 4 and an aqueous suspension (e) (pH 5.5) not containing microcrystalline cellulose carmellose sodium but otherwise identical with (a) were used as test drugs.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Description
- The present invention relates to a stabilized aqueous suspension of loteprednol etabonate having antiinflammatory and antiallergic activities for use as nasal drops.
- Loteprednol etabonate is a synthetic adrenocortical hormone having excellent antiinflammatory and antiallergic activities, and because of those activities coupled with a low dermal (mucosal) irritation potential and a low risk for side effects, this compound is expected to be of value as a drug for external application, e.g. an ointment or a liquid. EP-A-0709099 discloses a nasal composition comprising loteprednol etabonate and a thickener, in particular cyclodextrin or a cellulose derivative.
- However, since loteprednol etabonate is substantially insoluble in water, it has to be provided in the form of a suspension as far as a liquid dosage form for external application is concerned. Heretofore, as a suspending agent-stabilizer for such a water-insoluble (inclusive of hardly water-soluble) drug, methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose sodium (CMC-Na), or polyvinylpyrrolidone (PVP), for instance, has been generally employed. As far as loteprednol etabonate is concerned, however, none of said MC, HPMC, CMC-Na, and PVP in its usual formulating amount is capable of providing sufficiently stabilized suspensions. Thus, if such a suspension is allowed to stand for a long time, e.g. 3 months or longer, particles of loteprednol etabonate undergo aggregation and precipitation to form deposits on the container bottom and side walls and once this occurs, the original condition immediately after preparation cannot be reestablished even if the container is shaken or swirled vigorously. Of course, the concentration of the active ingredient in the suspension will be deviating from the concentration immediately after preparation. Furthermore, when the dosage form is nasal drops, the suspension is provided in the conventional nasal sprayer but the aggregation and deposition of particles take place in the nozzle part of the quantitative delivery pump to cause a failure to deliver the designed quantity or clogging of the nozzle orifices.
- Therefore, how an aqueous suspension of loteprednol etabonate could be kept stable over a long time has been an important question to be answered.
- From the above viewpoint, a stable aqueous suspension of loteprednol etabonate has been proposed by WO 95/11669. However, when the suspension is administered to a nasal cavity, it runs down from the nasal foramen because of its low viscosity less than 80 mPa·sec (80 centipoise). Therefore, the suspension has drawbacks that its retention time is too short to achieve pharmaceutical effect and that the feeling-of-use is not good.
- The inventor of the present invention explored the possibility of stabilizing an aqueous suspension of loteprednol etabonate and of improving intranasal retention of the active ingredients and the feeling-of-use using thickeners including cellulose derivatives such as methylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, etc., synthetic macromolecular compounds such as polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, etc., and saccharides such as sorbitol, mannitol, sucrose, etc.; cationic surfactants including quaternary ammonium salts; anionic surfactants including alkylsulfates; and nonionic surfactants including polysorbate 80, polyoxyethylene hydrogenated castor oil, etc. As a result, they discovered that microcrystalline cellulose carmellose sodium is not only highly effective in stabilizing a suspension of loteprednol etabonate but also has a low dermal (mucosal) irritation potential, a favorable feeling of use, and the property to enhance the muscosal retention of the active ingredient and, based on the finding, have developed the present invention. The present invention, therefore, is directed to:
- (1) an aqueous suspension for nasal administration which comprises loteprednol etabonate and microcrystalline cellulose carmellose sodium;
- (2) The aqueous suspension (1), which comprises 0.05-3 w/w % of loteprednol etabonate and 0.5-10 w/w % of microcrystalline cellulose carmellose sodium;
- (3) The aqueous suspension (1), which comprises 0.1-1.5 w/w % of loteprednol etabonate and 1-5 w/w % of microcrystalline cellulose carmellose sodium;
- (4) Use of an aqueous suspension comprising loteprednol etabonate and microcrystalline cellulose carmellose sodium for the manufacture of a medicament for nasal administration for treating inflammation or allergy.
- (5) The use according to (4), wherein the aqueous suspension for nasal administration comprises 0.05-3 w/w % of loteprednol etabonate and 0.5-10 w/w % of microcrystalline cellulose carmellose sodium.
- The concentration of loteprednol etabonate in the aqueous suspension for nasal administration according to the present invention is preferably 0.05-3 w/w % and more preferably 0.1-1.5 w/w %.
- Meanwhile, microcrystalline cellulose carmellose sodium is generally a mixture containing not less than 80 weight % of crystalline cellulose and 9-13 weight % of carmellose sodium. Though it depends on other additives present, its concentration in the aqueous suspension is preferably 0.5-10 w/w % and more preferably 1-5 w/w %.
- The aqueous suspension for nasal administration according to the present invention may contain, in addition to loteprednol etabonate, one or more other active substances such as a nonsteroidal antiinflammatory agent, e.g. mefenamic acid, an antihistaminic, e.g. clemastine fumarate, terfenadine, chlorpheniramine maleate, diphenhydramine hydrochloride, etc., an antiallergic agent such as tranilast, sodium cromoglycate, ketotifen fumarate, etc., an antibiotic, e.g. erythromycin, tetracycline, etc., and/or an antimicrobial agent, e.g. sulfamethizole, sulfamethoxazole, sulfisoxazole, etc., each in a suitable amount.
- The aqueous suspension for nasal administration according to the present invention may further contain other pharmacologically active substances, such as a vasoconstrictor, a surface anesthetic, etc., in suitable amounts. The vasoconstrictor includes but is not limited to naphazoline nitrate and phenylephrine hydrochloride. The surface anesthetic includes but is not limited to lidocaine, lidocaine hydrochloride, and mepivacaine hydrochloride. These pharmacologically active substances are used in a proportion of generally 0.01-10 w/w % and preferably 0.05-5 w/w %.
- The aqueous suspension for nasal administration according to the present invention may contain various additives which are broadly used in nasal drops in general. Among such additives are preservatives, isotonizing agents, buffers, stabilizers, pH control agents, and suspending agents. The preservative that can be used includes parabens (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, etc.), invert soaps (e.g. benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, etc.), alcohol derivatives (e.g. chlorobutanol, phenethyl alcohol, etc.), organic acids (e.g. dehydroacetic acid, sorbic acid, etc.), phenols (e.g. p-chloromethoxyphenol, p-chlorometacresol, etc.), and organomercury compounds (e.g. thimerosal, phenylmercury nitrate, nitromersol, etc.). The isotonizing agent includes but is not limited to glycerin, propylene glycol, sorbitol, and mannitol. The buffer that can be used includes boric acid, phosphoric acid, acetic acid, and amino acids, among others. The stabilizer includes antioxidants (e.g. dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, etc.), and chelating agents (edetic acid, citric acid, etc.). The pH control agent includes hydrochloric acid, acetic acid, sodium hydroxide, phosphoric acid, citric acid, etc. As the suspending agent, various surfactants (nonionic surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil, tyloxapol; cationic surfactants such as quaternary ammonium salts; anionic surfactants such as alkylsulfates; and amphoteric surfactants such as lecithin) can be employed.
- The addition levels of such additives vary with different active ingredients and their amounts but it is generally preferable that the physiological condition of the nose (isotonic to nasal discharge) be simulated. Typically, the osmotic pressure range should correspond to 0.2-4 w/w % saline, preferably 0.5-2 w/w % saline, and more preferably 0.9-1.5 w/w % saline.
- The aqueous suspension for nasal administration according to the present invention is preferably provided in the pH range generally used for nasal drops, i.e. pH 5-7.
- The aqueous suspension for nasal administration according to the present invention is provided in the osmotic pressure range used for nasal administration in general, generally 140-1140 mOsm, preferably 200-870 mOsm, and more preferably 280-310 mOsm.
- The aqueous suspension for nasal administration according to the present invention is preferably provided in the viscosity ranges so as to be well retained in the nasal cavity and so as not to be dripped down from the nasal foramen after administration, in general, 400-3000 mPa·sec (400-3000 centipoise), preferably, 1000-1000 mPa·sec (1000-1600 centipoise), and more preferably, 1200-1450 mPa·sec (1200-1450 centipoise).
- The aqueous suspension for nasal administration according to the present invention can be produced by the per se known technology. For example, it can be produced by the method described in Prescribing Guidelines IX (edited by Japanese Association of Pharmacists, 128-129, published by Yakuji Nippo, Ltd.).
- The aqueous suspension for nasal administration according to the present invention can be administered by the method employed for known nasal drops in general, for example by the spray method or the drip method. Taking the spray method as an example, although it depends on the patient's age, body weight and condition, the recommended dosage and administration for the therapy of allergic rhinitis or vasomotor rhinitis in an adult patient comprise sniffing 1-2 sprays from a nasal dispenser nozzle once or twice daily. When the drip method is employed, although it depends on the patient's age, body weight, and condition, the recommended dosage and administration for the therapy of allergic rhinitis in an adult comprise dripping 2-3 drops of an aqueous suspension of the invention, which contains 0.05-3.0 w/w % or preferably 0.1-1.5 w/w % of loteprednol etabonate, into the nostril in standing or sedentary position with the neck bent back with a frequency of 1-2 times daily.
- The following working and experimental examples are intended to further describe the invention and illustrate the effect of the invention.
-
Recipe Loteprednol etabonate 0.5 g Concentrated glycerin 2.6 g Polysorbate 80 0.2 g Microcrystalline cellulose carmellose sodium 2.0 g Citric acid q.s. Benzalkonium chloride 0.005 g Purified water to make 100 g (pH 5.5) - With a homomixer (6000 rpm), 90 g of purified water, 0.5 g of loteprednol etabonate, 2.6 g of concentrated glycerin, 0.5 ml of 1% benzalkonium chloride solution, and 0.2 g of polysorbate 80 were stirred for 30 minutes. To this liquid mixture was added 2.0 g of microcrystalline cellulose carmellose sodium("Avicel® RC-A591 NF", produced by Asahi Chemical Industry Co., Ltd.) and the whole mixture was further stirred with a mixer (750 rpm) for 60 minutes. This is followed by addition of a suitable amount of citric acid as well as purified water to bring the pH to 5.5. The mixture was further stirred for 10 minutes to provide 100 g of an aqueous suspension (a). The viscosity of the suspension measured with BL type viscometer (Number of revolution: 30 rpm, Adaptor NO. 3, produced by Tokimech Co., Ltd.) was 1160 mPa·sec (1160 centipoise).
-
Recipe Loteprednol etabonate 0.5 g Concentrated glycerin 2.6 g Polysorbate 80 0.2 g Microcrystalline cellulose carmellose sodium 3.0 g Citric acid q.s. Benzalkonium chloride 0.005 g Purified water to make 100 g (pH 5.5) - By the same procedure as described in Example 1, 100 g of an aqueous suspension (b) for nasal administration was prepared. The viscosity of the suspension was 1380 mPa·sec (1380 centipoise).
-
Recipe Loteprednol etabonate 1.0 g Concentrated glycerin 2.6 g Polysorbate 80 0.2 g Microcrystalline cellulose carmellose sodium 3.0 g Citric acid q.s. Benzalkonium chloride 0.005 g Purified water to make 100 g (pH 5.5) - By the same procedure as described in Example 1, 100 g of an aqueous suspension (c) for nasal administration was prepared. The viscosity of the suspension was 1440 mPa·sec (1440 centipoise).
-
Recipe Loteprednol etabonate 0.5 g Propylene glycol 2.0 g Polyoxyethylene hydrogenated castor oil 60 0.2 g Microcrystalline cellulose carmellose sodium 3.0 g Phosphoric acid q.s. Benzethonium chloride 0.005 g Purified water to make 100 g (pH 5.5) - By the same procedure as described in Example 1, 100 g of an aqueous suspension (d) for nasal administration was prepared. The viscosity of the suspension was 1340 mPa·sec (1340 centipoise).
- The aqueous suspensions (a) through (d) prepared in Examples 1 through 4 and an aqueous suspension (e) (pH 5.5) not containing microcrystalline cellulose carmellose sodium but otherwise identical with (a) were used as test drugs.
- Each of the above aqueous suspensions (a)-(e) was filled in 8 ml nasal sprayers and 5 panelists were instructed to spray 70 µl of the aqueous suspension into their nostrils and evaluate the feeling of use. The results are presented in Table 1.
[Table 1] Suspension Result (a) All of the 5 panelists reported neither drippings from the nose after application nor irritation (b) All of the 5 panelists reported neither drippings from the nose after application nor irritation (c) All of the 5 panelists reported neither drippings from the nose after application nor irritation (d) All of the 5 panelists reported neither drippings from the nose after application nor irritation (e) All of the 5 panelists reported discomfort with drippings from the nose after application. - The aqueous suspensions (a)-(e) prepared as above were respectively filled in polyethylene containers (8 ml) for nasal administration and the homogeneity of each suspension was evaluated immediately after preparation, on day 7 after preparation, and after 3 months of storage at 25°C. The results are presented in Table 2.
[Table 2] Suspension Immediately after preparation 7 days 3 momths (a) No floating crystals, with the water phase being thoroughly homogeneous No floating crystals, with the water phase being thoroughly homogeneous No floating crystals, with the water phase being thoroughly homogeneous (b) Do. Do. Do. (c) Do. Do. Do. (d) Do. Do. Do. (e) Some crystals were afloat on the water phase. Because some crystals was afloat on the water phase immediately after preparation, no further assessment was made. Because some crystals was afloat on the water phase immediately after preparation, no further assessment was made. - The aqueous suspension for nasal administration according to the present invention remains stable over a long period of time, without signs of aggregation, precipitation, or deposits of the active ingredient loteprednol etabonate particles. Moreover, after being sprayed into the nostrils, the suspension is well retained on the mucosal surface and does not drip. In addition, the suspension does not elicit an irritable response, offering a very satisfactory feeling of use.
Claims (5)
- An aqueous suspension for nasal administration which comprises loteprednol etabonate and microcrystalline cellulose carmellose sodium.
- The aqueous suspension for nasal administration according to claim 1, which contains 0.05-3 w/w % of loteprednol etabonate and 0.5-10 w/w % of microcrystalline cellulose carmellose sodium.
- The aqueous suspension for nasal administration according to claim 1, which contains 0.1-1.5 w/w % of loteprednol etabonate and 1-5 w/w % of microcrystalline cellulose carmellose sodium.
- Use of the aqueous suspensions according to any one of claims 1-3 for preparing a medicament for nasal administration for treating inflammation or allergy.
- The use according to claim 4, wherein the aqueous suspension for nasal administration comprises 0.05-3 w/w % of loteprednol etabonate and 0.5-10 w/w % of microcrystalline cellulose carmellose sodium.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1966497 | 1997-01-16 | ||
JP1966497 | 1997-01-16 | ||
PCT/JP1998/000108 WO1998031343A2 (en) | 1997-01-16 | 1998-01-14 | Aqueous suspension for nasal administration of loteprednol |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0973501A2 EP0973501A2 (en) | 2000-01-26 |
EP0973501B1 true EP0973501B1 (en) | 2003-09-10 |
Family
ID=12005518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98900360A Expired - Lifetime EP0973501B1 (en) | 1997-01-16 | 1998-01-14 | Aqueous suspension for nasal administration of loteprednol |
Country Status (33)
Country | Link |
---|---|
US (1) | US6368616B1 (en) |
EP (1) | EP0973501B1 (en) |
KR (1) | KR100471708B1 (en) |
CN (1) | CN1126535C (en) |
AR (1) | AR011773A1 (en) |
AT (1) | ATE249205T1 (en) |
AU (1) | AU730953C (en) |
BR (1) | BR9806771A (en) |
CA (1) | CA2278025C (en) |
CZ (1) | CZ294919B6 (en) |
DE (1) | DE69818026T2 (en) |
DK (1) | DK0973501T3 (en) |
EA (1) | EA001775B1 (en) |
ES (1) | ES2206880T3 (en) |
HK (1) | HK1026138A1 (en) |
HU (1) | HU226613B1 (en) |
ID (1) | ID21892A (en) |
IL (1) | IL130979A0 (en) |
LT (1) | LT4677B (en) |
LV (1) | LV12449B (en) |
MX (1) | MXPA99006628A (en) |
NO (1) | NO324619B1 (en) |
NZ (2) | NZ509908A (en) |
PL (1) | PL190753B1 (en) |
PT (1) | PT973501E (en) |
RS (1) | RS49701B (en) |
SI (1) | SI20057A (en) |
SK (1) | SK283164B6 (en) |
TR (1) | TR199901663T2 (en) |
TW (1) | TW503113B (en) |
UA (1) | UA52722C2 (en) |
WO (1) | WO1998031343A2 (en) |
ZA (1) | ZA98303B (en) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI243687B (en) | 1998-04-21 | 2005-11-21 | Teijin Ltd | Pharmaceutical composition for application to mucosa |
JP4338313B2 (en) * | 1998-08-26 | 2009-10-07 | 帝人株式会社 | Powdered nasal composition |
DE19947235A1 (en) * | 1999-09-30 | 2001-04-05 | Asta Medica Ag | New combination of loteprednol and beta¶2¶ adrenoreceptor agonists |
AR026073A1 (en) | 1999-10-20 | 2002-12-26 | Nycomed Gmbh | PHARMACEUTICAL COMPOSITION AQUATIC CONTAINING CICLESONIDE |
US6565832B1 (en) * | 2000-01-31 | 2003-05-20 | Schering-Plough Healthcare Products, Inc. | Spray composition with reduced dripping |
CN100391462C (en) * | 2001-06-18 | 2008-06-04 | 诺芬药品公司 | Enhanced drug delivery in transdermal systems |
GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
US8912174B2 (en) * | 2003-04-16 | 2014-12-16 | Mylan Pharmaceuticals Inc. | Formulations and methods for treating rhinosinusitis |
US7811606B2 (en) * | 2003-04-16 | 2010-10-12 | Dey, L.P. | Nasal pharmaceutical formulations and methods of using the same |
US9808471B2 (en) * | 2003-04-16 | 2017-11-07 | Mylan Specialty Lp | Nasal pharmaceutical formulations and methods of using the same |
WO2004112800A1 (en) * | 2003-06-19 | 2004-12-29 | Bodor Nicholas S | Enhancement of activity and/or duration of action of selected anti-inflammatory steroids |
ATE454154T1 (en) | 2003-06-19 | 2010-01-15 | Nicholas S Bodor | INCREASE THE ACTIVITY AND/OR DURATION OF EFFECT OF SOFT STEROIDS WITH ANTI-INFLAMMATORY ACTION FOR TOPICAL OR LOCAL ADMINISTRATION |
US20050095205A1 (en) * | 2003-10-31 | 2005-05-05 | Ramesh Krishnamoorthy | Combination of loteprednol etabonate and tobramycin for topical ophthalmic use |
ATE441419T1 (en) | 2004-03-25 | 2009-09-15 | Bausch & Lomb | USE OF LOTEPREDNOLE TABONATE TO TREAT DRY EYES |
US20070099883A1 (en) * | 2005-10-07 | 2007-05-03 | Cheryl Lynn Calis | Anhydrous mometasone furoate formulation |
WO2007058935A2 (en) * | 2005-11-14 | 2007-05-24 | Bausch & Lomb Incorporated | Ophthalmic composition for dry eye therapy |
US7687484B2 (en) * | 2006-05-25 | 2010-03-30 | Bodor Nicholas S | Transporter enhanced corticosteroid activity |
US7691811B2 (en) * | 2006-05-25 | 2010-04-06 | Bodor Nicholas S | Transporter-enhanced corticosteroid activity and methods and compositions for treating dry eye |
WO2012119261A1 (en) * | 2011-03-10 | 2012-09-13 | Biocia Inc. | Enhanced artificial mucus composition comprising hyaluronan for the treatment of rhinitis |
EP2758031A1 (en) | 2011-09-22 | 2014-07-30 | Bausch & Lomb Incorporated | Ophthalmic gel compositions |
CN111050750A (en) | 2017-08-24 | 2020-04-21 | 诺沃挪第克公司 | GLP-1 compositions and uses thereof |
MX2022009523A (en) | 2020-02-18 | 2022-09-09 | Novo Nordisk As | Pharmaceutical formulations. |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5540930A (en) * | 1993-10-25 | 1996-07-30 | Pharmos Corporation | Suspension of loteprednol etabonate for ear, eye, or nose treatment |
EP0709099A3 (en) * | 1994-09-28 | 1996-07-24 | Senju Pharma Co | An aqueous nasal suspension comprising cyclodextrin |
KR100508227B1 (en) | 1997-03-14 | 2006-03-23 | 센주 세이야꾸 가부시키가이샤 | Aqueous suspension of loteprednol etabonate |
-
1998
- 1998-01-06 TW TW087100103A patent/TW503113B/en not_active IP Right Cessation
- 1998-01-14 ES ES98900360T patent/ES2206880T3/en not_active Expired - Lifetime
- 1998-01-14 AT AT98900360T patent/ATE249205T1/en not_active IP Right Cessation
- 1998-01-14 NZ NZ509908A patent/NZ509908A/en unknown
- 1998-01-14 NZ NZ336990A patent/NZ336990A/en unknown
- 1998-01-14 PL PL334614A patent/PL190753B1/en not_active IP Right Cessation
- 1998-01-14 ID IDW990725A patent/ID21892A/en unknown
- 1998-01-14 AU AU54952/98A patent/AU730953C/en not_active Ceased
- 1998-01-14 ZA ZA98303A patent/ZA98303B/en unknown
- 1998-01-14 DK DK98900360T patent/DK0973501T3/en active
- 1998-01-14 KR KR10-1999-7006440A patent/KR100471708B1/en not_active IP Right Cessation
- 1998-01-14 CZ CZ19992374A patent/CZ294919B6/en not_active IP Right Cessation
- 1998-01-14 US US09/341,522 patent/US6368616B1/en not_active Expired - Fee Related
- 1998-01-14 TR TR1999/01663T patent/TR199901663T2/en unknown
- 1998-01-14 DE DE69818026T patent/DE69818026T2/en not_active Expired - Fee Related
- 1998-01-14 SI SI9820018A patent/SI20057A/en not_active IP Right Cessation
- 1998-01-14 IL IL13097998A patent/IL130979A0/en not_active IP Right Cessation
- 1998-01-14 PT PT98900360T patent/PT973501E/en unknown
- 1998-01-14 RS YUP-361/99A patent/RS49701B/en unknown
- 1998-01-14 WO PCT/JP1998/000108 patent/WO1998031343A2/en active IP Right Grant
- 1998-01-14 EA EA199900659A patent/EA001775B1/en not_active IP Right Cessation
- 1998-01-14 CA CA002278025A patent/CA2278025C/en not_active Expired - Fee Related
- 1998-01-14 BR BR9806771-0A patent/BR9806771A/en not_active IP Right Cessation
- 1998-01-14 UA UA99084658A patent/UA52722C2/en unknown
- 1998-01-14 HU HU0002473A patent/HU226613B1/en not_active IP Right Cessation
- 1998-01-14 EP EP98900360A patent/EP0973501B1/en not_active Expired - Lifetime
- 1998-01-14 SK SK948-99A patent/SK283164B6/en not_active IP Right Cessation
- 1998-01-14 CN CN98803402A patent/CN1126535C/en not_active Expired - Fee Related
- 1998-01-14 MX MXPA99006628A patent/MXPA99006628A/en not_active IP Right Cessation
- 1998-01-16 AR ARP980100191A patent/AR011773A1/en active IP Right Grant
-
1999
- 1999-07-13 NO NO19993453A patent/NO324619B1/en not_active IP Right Cessation
- 1999-07-15 LV LVP-99-109A patent/LV12449B/en unknown
- 1999-08-12 LT LT99-100A patent/LT4677B/en not_active IP Right Cessation
-
2000
- 2000-07-26 HK HK00104645A patent/HK1026138A1/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0973501B1 (en) | Aqueous suspension for nasal administration of loteprednol | |
EP0742714B1 (en) | Liquid pharmaceutical compositions comprising thyroid hormones | |
AU2012204557B2 (en) | Bepotastine compositions | |
CA1288048C (en) | Aqueous steroid formulations for nasal administration | |
EP0938896A1 (en) | Autoclavable pharmaceutical compositions containing a chelating agent | |
EP0709099A2 (en) | An aqueous nasal suspension comprising cyclodextrin | |
PL175860B1 (en) | Ophtalmic preparation | |
JP4453987B2 (en) | Nasal aqueous suspension | |
US20220370445A1 (en) | Methods for administering (r)-n-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide | |
US20090142321A1 (en) | Opthalmic composition | |
JP2003055201A (en) | Solubilized composition containing vitamin a compounds and method for stabilizing vitamin a compounds | |
JP2001131055A (en) | Liquid agent, removal of white cloudiness of liquid agent and acceleration of trans-mucous membrane absorption of liquid agent | |
JPH08151332A (en) | Aqueous suspension for nasal drop | |
US20160338951A1 (en) | Process of preparing aqueous ophthalmic solution of olopatadine | |
NZ616149B2 (en) | Nasal Pharmaceutical Formulation Comprising Fluticasone | |
IT9048064A1 (en) | CALCITONIN-BASED PHARMACEUTICAL COMPOSITIONS ADMINISTRABLE BY NASAL WAY IN HUMAN THERAPY |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19990713 |
|
AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
17Q | First examination report despatched |
Effective date: 20010828 |
|
GRAH | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOS IGRA |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REF | Corresponds to: |
Ref document number: 69818026 Country of ref document: DE Date of ref document: 20031016 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: T3 |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20030405059 Country of ref document: GR |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2206880 Country of ref document: ES Kind code of ref document: T3 |
|
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1026138 Country of ref document: HK |
|
ET | Fr: translation filed | ||
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20040614 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PUE Owner name: NICHOLAS BODOR Free format text: SENJU PHARMACEUTICAL CO., LTD.#5-8, HIRANOMACHI 2-CHOME, CHUO-KU#OSAKA-SHI, OSAKA 541-0046 (JP) -TRANSFER TO- NICHOLAS BODOR#3929 SW 69TH AVENUE#GAINESVILLE, FL 32608 (US) Ref country code: CH Ref legal event code: NV Representative=s name: A. BRAUN, BRAUN, HERITIER, ESCHMANN AG PATENTANWAE |
|
NLS | Nl: assignments of ep-patents |
Owner name: NICHOLAS BODOR |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: PC4A Owner name: NICHOLAS BODOR, US Effective date: 20050523 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: ES Payment date: 20071227 Year of fee payment: 11 |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: 732E |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20080128 Year of fee payment: 11 Ref country code: GB Payment date: 20080109 Year of fee payment: 11 Ref country code: DE Payment date: 20080307 Year of fee payment: 11 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PFA Owner name: NICHOLAS BODOR Free format text: NICHOLAS BODOR#3929 SW 69TH AVENUE#GAINESVILLE, FL 32608 (US) -TRANSFER TO- NICHOLAS BODOR#3929 SW 69TH AVENUE#GAINESVILLE, FL 32608 (US) |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: FR Payment date: 20080115 Year of fee payment: 11 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: TP |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: MC Payment date: 20081218 Year of fee payment: 12 Ref country code: IE Payment date: 20081201 Year of fee payment: 12 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: PC2A |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: PT Payment date: 20081119 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: BE Payment date: 20081208 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20090126 Year of fee payment: 12 Ref country code: DK Payment date: 20090112 Year of fee payment: 12 Ref country code: AT Payment date: 20081128 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20090131 Year of fee payment: 12 Ref country code: FI Payment date: 20090109 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: GR Payment date: 20081121 Year of fee payment: 12 Ref country code: CH Payment date: 20090128 Year of fee payment: 12 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: SE Payment date: 20090115 Year of fee payment: 12 |
|
GBPC | Gb: european patent ceased through non-payment of renewal fee |
Effective date: 20090114 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090801 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: ST Effective date: 20091030 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090114 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20090115 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090202 Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090115 |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: MM4A Free format text: LAPSE DUE TO NON-PAYMENT OF FEES Effective date: 20100714 |
|
BERE | Be: lapsed |
Owner name: *BODOR NICHOLAS Effective date: 20100131 |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: V1 Effective date: 20100801 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100131 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EBP |
|
EUG | Se: european patent has lapsed | ||
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MM4A |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100801 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100131 Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100131 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: FI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100114 Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100114 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100714 Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100114 Ref country code: DK Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100131 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100131 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090114 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: SE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100115 Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20100114 |